Disease-associated fibronectin matrix fragments trigger anoikis of human primary ligament cells: p53 and c-myc are suppressed

Dai, Ruo-Lian; Iwama, Akihiro; Wang, S.; Kapila, Yvonne L.

doi:10.1007/s10495-005-1880-5

Cited by 28 publications

(35 citation statements)

References 19 publications

(23 reference statements)

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“…This breakdown product of fibronectin originates from the proteolytic cleavage of intact fibronectin, and it is found in the gingival crevicular fluid of patients affected by periodontal disease and in joint fluids from arthritic patients (29,33). Our earlier studies showed that this proteolytic fragment and its recombinant counterpart, AFn, trigger aberrant cell signaling in primary cells that ultimately leads to apoptosis (13,40,68). In addition, the breakdown products of macromolecules generate nitric oxide in cells present in inflamed sites.…”

Section: Discussionmentioning

confidence: 99%

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Porphyromonas gingivalis, Gamma Interferon, and a Proapoptotic Fibronectin Matrix Form a Synergistic Trio That Induces c-Jun N-Terminal Kinase 1-Mediated Nitric Oxide Generation and Cell Death

Ghosh¹,

Park²,

Fenno

et al. 2008

Infect Immun

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During infection and inflammation, bacterial and inflammatory proteases break down extracellular matrices into macromolecular fragments. Fibronectin fragments are associated with disease severity in arthritis and periodontitis. The mechanisms by which these fragments contribute to disease pathogenesis are unclear. One likely mechanism is that fibronectin fragments induce apoptosis of resident cells, which can be further modulated by nitric oxide. Nitric oxide levels are increased at inflammatory sites in periodontitis patients. The aim of this study was to examine whether a proapoptotic fibronectin matrix (AFn) exerts its action by inducing nitric oxide and whether priming by bacterial and inflammatory components exacerbates this mechanism. Our data demonstrate that AFn increased the levels of nitric oxide and inducible nitric oxide synthase (iNOS) dose and time dependently in periodontal ligament (PDL) cells. These effects and apoptosis were inhibited by iNOS suppression and enhanced by iNOS overexpression. Nitric oxide and iNOS induction were paralleled by increased c-Jun N-terminal kinase 1 (JNK-1) phosphorylation. JNK-1 overexpression enhanced the expression of nitric oxide and iNOS, whereas inhibiting JNK-1 by small interfering RNA or a kinase mutant reversed these findings. Priming PDL cells with Porphyromonas gingivalis, its lipopolysaccharide (LPS), or gamma interferon (IFN-␥) further increased nitric oxide levels and apoptosis. Escherichia coli and Streptococcus mutans induced lesser effects. Gingival fibroblasts and neutrophils responded to a lesser degree to these stimuli, whereas keratinocytes were resistant to apoptosis. Thus, proapoptotic matrices trigger nitric oxide release via JNK-1, promoting further apoptosis in host cells. LPS and IFN-␥ accentuate this mechanism, suggesting that during inflammation, the affected matrices and bacterial and inflammatory components combined exert a greater pathogenic effect on host cells.

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Section: Discussionmentioning

confidence: 99%

“…We previously identified a recombinant altered fibronectin molecule and a comparable disease-associated proteolytic fibronectin fragment that induce apoptosis in primary cells, including PDL cells (13,68). This apoptotic process is unique since it is accompanied by a downregulation of p53 at both the transcriptional and the posttranslational level.…”

mentioning

confidence: 99%

Porphyromonas gingivalis, Gamma Interferon, and a Proapoptotic Fibronectin Matrix Form a Synergistic Trio That Induces c-Jun N-Terminal Kinase 1-Mediated Nitric Oxide Generation and Cell Death

Ghosh¹,

Park²,

Fenno

et al. 2008

Infect Immun

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“…32 The V þ HÀ fragment is comparable to the 40 kDa naturally occurring proteolytic fragment found in diseased patient fluids. 33,34 Both fragments rely on interactions with the heparin-binding domain and V region of FN.…”

Section: Methodsmentioning

confidence: 99%

NG2, a novel proapoptotic receptor, opposes integrin α4 to mediate anoikis through PKCα-dependent suppression of FAK phosphorylation

et al. 2008

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Disruption of cell-matrix interactions can lead to anoikis -apoptosis due to loss of matrix contacts. Altered fibronectin (FN) induces anoikis of primary human fibroblasts by a novel signaling pathway characterized by reduced phosphorylation of focal adhesion kinase (FAK). However, the receptors involved are unknown. FAK phosphorylation is regulated by nerve/glial antigen 2 (NG2) receptor signaling through PKCa a point at which signals from integrins and proteoglycans may converge. We found that an altered FN matrix induced anoikis in fibroblasts by upregulating NG2 and downregulating integrin a4. Suppressing NG2 expression or overexpressing a4 rescued cells from anoikis. NG2 overexpression alone induced apoptosis and, by reducing FAK phosphorylation, increased anoikis induced by an altered matrix. NG2 overexpression or an altered matrix also suppressed PKCa expression, but overexpressing integrin a4 enhanced FAK phosphorylation independently of PKCa. Cotransfection with NG2 cDNA and integrin a4 siRNA did not lower PKCa and pFAK levels more than transfection with either alone. PKCa was upstream of FAK phosphorylation, as silencing PKCa decreased FAK phosphorylation. PKCa overexpression reversed this behavior and rescued cells from anoikis. Thus, NG2 is a novel proapoptotic receptor, and NG2 and integrin a4 oppositely regulate anoikis in fibroblasts. NG2 and integrin a4 regulate FAK phosphorylation by PKCa-dependent and -independent pathways, respectively. Cell Death and Differentiation (2008) The extracellular matrix (ECM) glycoprotein fibronectin (FN) affects adhesion, migration, survival, and other cellular functions. FN fragments found in vivo and associated with disease or comparable recombinant fragments trigger apoptosis/anoikis in primary human fibroblasts via a novel pathway regulated by decreases in focal adhesion kinase (FAK) phosphorylation and downregulation of p53.1-3 However, the receptors involved are not known. Two classes of cellsurface receptors, integrins and proteoglycans, interact with FN and could mediate the anoikis. This process is regulated by FAK, an integrin-dependent non-receptor tyrosine kinase, consistent with a role for integrins. Also proteoglycans are involved in this apoptotic mechanism. 1Integrins are a and b heterodimeric cell-surface receptors that mediate cell-ECM interactions and regulate cell adhesion, migration, proliferation, and survival. Interactions between FN and integrins promote the survival of many cell types. We showed that blocking antibodies against the a4 integrin subunit induced apoptosis-like cell rounding in human fibroblasts, similar to that induced by anoikis in response to an altered FN matrix fragment.2 Integrins mediate those responses by binding ECM ligands and activating signaling cascades that promote these actions. The a4 integrin subunit can bind to at least three interaction sites on FN. These include the arginine-glycine-aspartic acid site on the central cell-binding domain, the V region, and the heparin-binding domain. Once engaged, integrins ...

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“…6A-C). Certain fibronectin fragments can promote inflammation (Barilla and Carsons, 2000;Norris et al, 1982), whereas other fibronectin fragments are known to regulate cell migration, growth and survival (Clark et al, 1988;Dai et al, 2005;Homandberg et al, 1985). Therefore, tight regulation of ECM fibronectin degradation and endocytosis provides a mechanism for limiting the accumulation of bioactive matrix fragments.…”

Section: Mt1-mmp Regulates Fibronectin Turnover 4045mentioning

confidence: 99%

MT1-MMP regulates the turnover and endocytosis of extracellular matrix fibronectin

Shi

Sottile

2011

Journal of Cell Science

108

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SummaryThe extracellular matrix (ECM) is dynamically remodeled by cells during development, normal tissue homeostasis and in a variety of disease processes. We previously showed that fibronectin is an important regulator of ECM remodeling. The deposition and/or polymerization of fibronectin into the ECM controls the deposition and stability of other ECM molecules. In addition, agents that inhibit fibronectin polymerization promote the turnover of fibronectin fibrils and enhance ECM fibronectin endocytosis and intracellular degradation. Endocytosis of ECM fibronectin is regulated by b1 integrins, including a5b1 integrin. We have examined the role of extracellular proteases in regulating ECM fibronectin turnover. Our data show that membrane type matrix metalloproteinase 1 (MT1-MMP; also known as MMP14) is a crucial regulator of fibronectin turnover. Cells lacking MT1-MMP show reduced turnover and endocytosis of ECM fibronectin. MT1-MMP regulates ECM fibronectin remodeling by promoting extracellular cleavage of fibronectin and by regulating a5b1-integrin endocytosis. Our data also show that fibronectin polymerization stabilizes fibronectin fibrils and inhibits ECM fibronectin endocytosis by inhibiting a5b1-integrin endocytosis. These data are the first to show that an ECM protein and its modifying enzyme can regulate integrin endocytosis. These data also show that integrin trafficking plays a major role in modulating ECM fibronectin remodeling. The dual dependence of ECM fibronectin turnover on extracellular proteolysis and endocytosis highlights the complex regulatory mechanisms that control ECM remodeling to ensure maintenance of proper tissue function.

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Disease-associated fibronectin matrix fragments trigger anoikis of human primary ligament cells: p53 and c-myc are suppressed

Cited by 28 publications

References 19 publications

Porphyromonas gingivalis, Gamma Interferon, and a Proapoptotic Fibronectin Matrix Form a Synergistic Trio That Induces c-Jun N-Terminal Kinase 1-Mediated Nitric Oxide Generation and Cell Death

Porphyromonas gingivalis, Gamma Interferon, and a Proapoptotic Fibronectin Matrix Form a Synergistic Trio That Induces c-Jun N-Terminal Kinase 1-Mediated Nitric Oxide Generation and Cell Death

NG2, a novel proapoptotic receptor, opposes integrin α4 to mediate anoikis through PKCα-dependent suppression of FAK phosphorylation

MT1-MMP regulates the turnover and endocytosis of extracellular matrix fibronectin

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